Of the estimated 43 million individuals with hypertension in the US, perhaps half demonstrate salt sensitivity. Approximately 1 in 2500 also suffers from clinically important end-organ kidney damage. The problem is enormously significant, but the pathogenesis of salt-sensitive hypertension and hypertensive nephrosclerosis remains poorly defined. Work supported during the previous funding cycle of this grant has shown a direct effect of dietary salt on arterial endothelium and kidney under normal and pathological conditions. An increase in dietary salt controls nitric oxide (NO) production in normotensive rats by increasing expression of endothelial (NOS3) and inducible (NOS2) NO synthases in the vasculature and kidney. In addition, a coordinated expression of NOS3 and transforming growth factor-B1 (TGF-B1) in aortic endothelium and glomeruli occurs in normotensive animals during changes in dietary salt intake. The Dahl/Rapp salt-sensitive (S) strain of rat provides an ideal genetic model of salt-sensitive hypertension. The working hypothesis in this proposal is that dietary salt profoundly affects signal transduction events in the vascular endothelium and kidney, leading to production of effector molecules that include NOS2, NOS3 and TGF-B1. In so doing, blood pressure and the renal response to dietary salt intake are modulated. In salt-sensitive individuals, the coordinated expression of these factors is altered to result in salt-sensitive hypertension. Three aims are proposed: 1) determine the role of the mitogen-activated protein kinase (MAPK) in aortic endothelium and kidney of Sprague-Dawley (SD) rats when dietary salt is increased; 2) determine the interaction and roles of NOS3 and TGF-B1 in the development of hypertensive nephrosclerosis in S rats; and 3) define the role of NF-KB activation in aortic endothelium and kidney cortex, outer medulla and inner medulla in rats while on a diet high in salt, with a focus on NOS2. Experiments have been designed to demonstrate the mechanism of activation and functional consequences of the MAPK and NF-KB pathways during changes in dietary salt. The long-term goal of this proposal will be to determine how the kidney and vasculature respond to an increase in dietary salt in normotensive states and during development of salt-sensitive hypertension.